Abstract Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade, metastasizing neoplasm characterized by the progressive infiltration of lung parenchyma with abnormal smooth muscle cells. LAM can be seen in association with Tuberous Sclerosis Complex (TSC-LAM), or occur sporadically (S-LAM). Both TSC- LAM and S-LAM occur as a result of mutations in one of the two TSC genes leading to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, which drives cell proliferation and lymphangiogenesis (in part) through production of vascular endothelial growth factors - VEGF-C and VEGF-D. Sirolimus binds to mTOR and blocks activation of downstream kinases, restoring homeostasis in cells with defective TSC function. In a recent study, sirolimus was shown to stabilize lung function decline and improve quality of life in patients with LAM. However, lung function decline resumed, and VEGF-D levels increased again, after stopping sirolimus, suggesting that the role of sirolimus is suppressive rather than remission inducing. In addition, the long term safety and efficacy of sirolimus in LAM remains unclear. These limitations of sirolimus highlight the critical need to explore novel treatment options for patients with LAM. Resveratrol is a naturally occurring polyphenol and has been shown to inhibit the activities of mTOR, Akt, and S6K1. Recent pre-clinical studies performed on TSC2 null cells and murine models have demonstrated that a combination of resveratrol and sirolimus leads to downregulation of autophagy and promotes apoptosis in TSC2 null cells, decreases the metastatic capability of uterine leiomyoma-derived smooth muscle cells, and causes a significant reduction in the size and growth of TSC2 deficient xenograft tumors. We hypothesize that treatment of LAM patients with a combination of sirolimus and resveratrol will be well tolerated and more effective than sirolimus alone. However, we need to determine the most effective and well-tolerated dose of resveratrol in LAM. Thus, we plan to conduct an open-label, dose- escalating, phase II safety and efficacy study of a combination of sirolimus and resveratrol in patients with LAM who are previously on a stable regimen of sirolimus. Specific aim 1 of our proposal will assess the change in serum VEGF-D after 24 weeks of treatment with resveratrol and sirolimus, as compared to the baseline VEGF-D level in patients on a stable dose of sirolimus alone. Specific aim 2 will determine the safety of combined resveratrol and sirolimus in patients with LAM. Specific aim 3 will assess the effect of resveratrol and sirolimus on lung function and quality of life. Our project is highly significant as it proposes the trial of a remission inducing (cytotoxic) as opposed to a suppressive (cytostatic) treatment option for patients with LAM. Successful completion of our study will determine the optimal dose of resveratrol in LAM, and provide information that is both necessary and sufficient in order to design a definitive, multicenter, randomized, controlled clinical trial of combined resveratrol and sirolimus in LAM.